The specific aims of the proposed project are designed to investigate whether physiological toxicity of glutamate on the mouse ear augments damage due to sound over-exposure, and whether molecular blockers to glutamate and nitric oxide (NO) can ameliorate these detrimental effects. In addition, the very important question of genetic susceptibility will also be addressed by using three inbred strains of mice that exhibit age-related hearing loss (AHL). It is also proposed in this project to develop a good mammalian model of the ear to test gene transfer therapies. Auditory functionality will be tested with distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABRs). These are two physiological measures of hearing ability that will be used to answer the very important clinical question of whether reagents that inhibit glutamate, and NO release or their aciton on their respective molecular receptor(s) can ameliorate noise-induced trauma to the mammalian inner ear. In addition, DPOAEs and ABR will be used to monitor auditory response of the mouse ear after infusion with viral particles. The specific aims are (1) to determine if microperfused glutamate augments damage to the sound over-exposed mouse ear, particularly the inner and outer hair cells, (2) to determine if memantine, a glutamate blocker, and/or NG-methyI-Larginine (L-NAME), a nitric oxide inhibitor, ameliorate functional decrements to the mouse ear due to sound over-exposure, (3) to determine if genetic components that result in different onsets of age-related hearing loss (AHL) are affected by glutamate and (4) to develop a genetically-important mammalian model to test viral infusion into the ear. Because the mouse had emerged as an important genetic mammalian model, it is anticipated that the proposed project will shed light, not only on the possible mechanism(s) of genetic susceptibility of age-related hearing loss in humans, but on possible ways to diminish age- and noiseinduced hearing loss by inhibiting toxic substances such as gluatamate and/or NO and by developing a model to test gene therapies before they go to clinical trials.